The problem with defaulting to the 3-plus-3 approach is it has a well-known flaw: more patients than necessary are exposed to doses that are either too high or too low. Other designs, like the accelerated titration design and the model-based design, expose fewer patients to subtherapeutic doses or overdosages.5

For Jonathan Kimmelman, PhD, director of the biomedical ethics unit at McGill University, Montreal, Québec, the decision to use the 3-plus-3 approach when other designs are available is a matter of ethics. “To my mind, that is ethically dubious to be using an outmoded design that is exposing more patients than needed to an unsafe and ineffective drug,” he told this publication.

American Society of Clinical Oncology (ASCO) President Howard A. Burris III, MD, told Cancer Therapy Advisor that researchers continue to use the 3-plus-3 designs because the other designs can be complex and pose a challenge for most researchers to “fully grasp,” given that they are often based on statistical or probability theory and the model-based designs, in particular, take time to develop.

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“It’s easy. It’s the conventional thing to do,” Dr Beumer said about the 3-plus-3 design. “Any physician can do it.”

The Real Problem

However, according to certain experts, the favoring of the 3-plus-3 design over other designs is not the real problem. The real problem is that all the designs focus on the same — arguably wrong — measure: MTD. “We don’t really care what the MTD is — that’s not the right dose,” said Dr Ratain.

Similar to how the 3-plus-3 approach is a remnant of the cytotoxic agent era, so too is MTD. When cytotoxic agents were being developed, the belief was that efficacy and toxicity were correlated with dose.5 “For a long time, the approach to curing cancer has been to give the largest dose possible,” said David Norris, MD, Precision Methodologies, LLC.

This belief, however, does not extend to molecularly targeted agents because these agents attack tumor-specific pathways, with the thought that this approach minimizes the negative effects of the agent on healthy tissue.5 Instead, the right dose could be one that exposes a patient to a therapeutically relevant amount, which can be determined by measuring the drug concentrations in the plasma — a practice also known as therapeutic drug monitoring.

“For every patient, that means a different dose,” Dr Beumer said. “The whole concept of measuring drug levels and adjusting doses based on that, even though in other therapeutic fields is very common, like transplant medicine — it’s just not done in oncology.”

At present, the oncology field lacks the infrastructure needed for routine therapeutic drug monitoring. To have routine therapeutic drug monitoring, the ideal target ranges for dose exposure would need to be established, laboratory tests to measure plasma drug concentrations would need to be developed, oncologists would need to be trained for this type of monitoring, and logistics would need to be worked out, such as when to collect plasma samples at what time points.7 Also, Dr Beumer said, “Pharma companies don’t have an incentive to target the concentration range because it makes the usage of their product in the marketplace so much harder.”

Despite the barriers to a more individualized dose, a select few individuals are trying to stimulate change in the way investigators seek and clinicians select dosage levels. Researchers are identifying optimal concentration ranges for an increasing number of cancer drugs, with one of the latest examples being sunitinib.8

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A critic of the current one-size-fits-all dosing practice and proponent for dose individualization, Dr Norris has been publishing about the topic for the past few years, and earlier this year submitted an open letter to the Director of Oncology Center of Excellence (OCE) at the US Food and Drug Administration, Richard Pazdur, MD, urging the OCE to take a stance on whether the traditional one-size-fits-all dose finding is truly compatible with the OCE’s mission.

During a phone interview with this publication, Anne Loeser, a patient living with metastatic breast cancer, explained that she and several other patients are promoting the idea of patient-centered dosing, in which a patient’s preferences and abilities are considered when selecting a dose in the clinic. This team of patients is constructing a list of criteria to consider, and so far, the preliminary list has 10 criteria, such as a patient’s side-effect history from previous drugs, whether disease has spread to the brain, and the availability of a patient’s caregiver.

However, Anne acknowledged that the work they are doing, while important, may not help overhaul the design of clinical trials. “You could call it a Band-Aid,” she said. “It’s not fixing the root cause.”


  1. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.
  2. Prasad V. 2.32 BONUS! Clinical Trials Part 1: Thinking Better About Cancer Medicine. Plenary Session [podcast]. January 2020. 
  3. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327.
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